NMN and TMG are commonly taken together because they support two connected processes. NMN supplies a building block the body can use to make NAD+, while TMG provides methyl groups involved in methylation and homocysteine metabolism. Still, there is no strong human evidence showing that everyone who takes NMN also needs TMG.

That last point matters. You will see plenty of claims that NMN "drains" methyl groups and TMG must replace them. The biology behind the idea makes sense, but human research tells a more nuanced story.

Key Takeaways:

• NMN is a precursor the body can use to produce NAD+, a molecule involved in cellular energy metabolism and many other processes.

• TMG, also called trimethylglycine or betaine, can donate methyl groups and help convert homocysteine back into methionine.

• NMN supplementation can increase methylated nicotinamide metabolites, but this does not prove that it causes harmful methyl depletion. (1)

• There is no established clinical NMN-to-TMG ratio, and researchers have not shown that TMG makes NMN work better.

What Are NMN and TMG?

NMN and TMG do different jobs, but their metabolic pathways cross paths. That connection is why the two supplements frequently end up in the same conversation.

NMN

Nicotinamide mononucleotide, better known as NMN, is a molecule involved in the body's production of nicotinamide adenine dinucleotide, or NAD+.

NAD+ participates in cellular energy metabolism and also serves as a substrate for enzymes involved in cell signaling and other biological processes.

Human research shows that supplemental NMN can influence NAD+ metabolism. In one randomized trial, 25 postmenopausal women with prediabetes received either placebo or 250 mg of NMN daily for 10 weeks. 

NMN increased NAD+ in peripheral blood mononuclear cells and increased several methylated nicotinamide metabolites. Muscle insulin sensitivity also improved by about 25% in the NMN group, although body composition, fasting glucose, blood pressure and several other metabolic measures did not change. (1)

So NMN is not simply an "energy supplement." Its metabolism involves a fairly busy network of pathways.

TMG

TMG stands for trimethylglycine. You may also see it called betaine.

TMG contains three methyl groups, which explains the name. In the body, it can donate one of these methyl groups to homocysteine through the betaine-homocysteine methyltransferase pathway.

That reaction helps convert: Homocysteine → Methionine

Methionine can then contribute to the production of S-adenosylmethionine, or SAM, one of the body's major methyl donors.

Human trials give us fairly solid evidence that supplemental TMG can influence homocysteine. One dose-response study involving 34 healthy adults found that 3 g and 6 g of betaine per day lowered plasma homocysteine by about 10% and 14%, respectively, while the reduction with 1 g was not statistically significant. (2)

That evidence tells us something useful about TMG itself. It does not, however, tell us that everyone taking NMN needs it.

Why Do People Take TMG With NMN?

The NMN and TMG pairing mostly comes down to what happens after NAD+ gets used.

NAD+ does not stay intact forever. Enzymes consume it during normal cellular processes and can leave behind nicotinamide, sometimes shortened to NAM.

Some of that nicotinamide can be recycled back into the NAD+ pathway. Some can also be processed by an enzyme called nicotinamide N-methyltransferase, or NNMT.

NNMT transfers a methyl group from SAM to nicotinamide:

Nicotinamide + SAM → Methylated nicotinamide + SAH

SAH can later contribute to homocysteine formation.

Here is where TMG enters the picture. TMG can donate a methyl group through a separate pathway that helps convert homocysteine back toward methionine.

That creates a sensible theory:

More NAD+ turnover could mean more nicotinamide to process. More nicotinamide methylation could increase demand for methyl groups. TMG supplies methyl groups and supports homocysteine remethylation.

The first parts of that pathway are well established. The leap comes when someone turns the theory into "NMN depletes methyl groups, so everyone needs TMG."

Current human research has not demonstrated that.

Does NMN Deplete Methyl Groups?

We do not currently have good human evidence showing that standard NMN supplementation causes clinically meaningful methyl-group depletion.

There are, however, reasons scientists have looked into the question.

In the 10-week NMN trial mentioned earlier, researchers found increased levels of N-methylnicotinamide and other methylated nicotinamide metabolites in skeletal muscle after participants took 250 mg of NMN daily. (1)

This tells us that NMN supplementation affected nicotinamide metabolism and methylation.

It does not tell us that the participants became deficient in methyl groups.

An interesting clue comes from research on nicotinamide riboside, or NR. NR is not NMN, so the findings cannot be copied directly across. Both compounds, however, feed into NAD+ metabolism.

In a randomized trial involving people with Parkinson's disease, participants received a very high 3,000 mg daily dose of NR for four weeks. Blood NAD+ rose by as much as fivefold. 

Serum homocysteine showed a small initial increase, yet researchers found no change in whole-blood SAM, SAH, the SAM-to-SAH ratio, methionine, or other evidence that the methyl-donor pool had been depleted. (3)

That is an important piece of the puzzle. Even under a high NAD+ precursor dose, the body appeared able to maintain its methyl-donor pool during the four-week study.

We still need NMN-specific research measuring these same markers over longer periods. Until that exists, statements that NMN "uses up your methyl groups" go further than the evidence allows.

What Are the Potential Benefits of Taking TMG With NMN?

There has not been a good randomized human trial comparing NMN alone versus NMN plus TMG. So claims about the combination need to stay grounded in what we know about TMG itself.

TMG Supports Methylation

Methylation happens throughout the body and contributes to processes involving DNA regulation, neurotransmitter metabolism, phospholipid production and many other reactions.

TMG supports one route for recycling homocysteine into methionine. Methionine can then contribute to SAM production.

This makes TMG a legitimate methyl donor. It does not mean taking more TMG automatically improves methylation or makes NMN more effective.

Your body also receives methyl-related nutrients from food, including folate, vitamin B12, choline, methionine and betaine itself.

TMG Can Help Lower Homocysteine

This is where the evidence behind TMG becomes much stronger.

One six-week randomized study looked at people with mildly elevated homocysteine. Participants received either 6 g of betaine, 800 mcg of folic acid, or placebo each day.

Relative to placebo, fasting homocysteine fell by 1.8 μmol/L in the betaine group. TMG also reduced the rise in homocysteine following a methionine-loading test. (4)

A later meta-analysis of five randomized controlled trials found that betaine supplementation reduced plasma homocysteine by an average of 1.23 μmol/L. The included studies used at least 4 g per day for 6 to 24 weeks. (5)

That does not mean high-dose TMG belongs in everyone's supplement routine. It simply gives us much firmer evidence for TMG's effect on homocysteine than for claims that it improves NMN supplementation.

TMG May Make More Sense for Some People

There is a big difference between "TMG has a role in methylation" and "everyone needs extra TMG."

Someone with elevated homocysteine, for example, has a different starting point from someone whose levels are comfortably within range.

Diet matters as well. Betaine occurs naturally in foods, while choline, folate, vitamin B12 and methionine interact with related methylation pathways.

For someone seriously concerned about methylation or homocysteine, a blood test and discussion with a healthcare professional can tell you far more than guessing based on an NMN dose.

Do You Need TMG If You Take NMN?

No, current evidence does not show that you need TMG simply because you take NMN.

Taking the two together is biologically reasonable. TMG provides methyl groups, and increased NAD+ metabolism can produce nicotinamide that may undergo methylation.

What is missing is the clinical link.

We do not yet have human trials demonstrating that:

• Standard NMN doses cause harmful methyl depletion.

• Adding TMG prevents a problem caused by NMN.

• NMN plus TMG increases NAD+ more than NMN alone.

• TMG improves the healthy-aging effects of NMN.

• Everyone taking NMN benefits from additional methyl donors.

That distinction gets lost surprisingly easily online.

The pathway explains why researchers might want to investigate the combination. It does not prove the combination is required.

How Much TMG Should You Take With NMN?

There is no scientifically established NMN-to-TMG ratio.

You may come across a 1:1 approach, such as:

• 250 mg NMN + 250 mg TMG

• 500 mg NMN + 500 mg TMG

• 1,000 mg NMN + 1,000 mg TMG

That ratio is easy to remember, but no clinical trial has established 1:1 as the ideal amount.

There is another wrinkle here. Most studies showing clear reductions in homocysteine used TMG doses measured in grams, not a few hundred milligrams. 

For example, the dose-response study discussed above found significant reductions with 3 g and 6 g daily, while 1 g did not produce a statistically significant reduction. (2)

That does not mean an NMN user should take 3 to 6 g. Those studies were designed to investigate homocysteine, not NMN supplementation.

If you want a closer look at the logic behind common dosing approaches, our breakdown of the NMN and TMG ratio explains where the 1:1 idea comes from and why it should not be treated as a fixed rule.

When Should You Take NMN and TMG?

There is no proven requirement to swallow NMN and TMG at exactly the same time.

They do not need to arrive in your stomach together for their metabolic pathways to function.

For NMN, morning is a sensible schedule because several human trials have successfully used morning dosing. Research has not established one perfect time of day, though, so consistency may be more useful than chasing a precise hour. You can read more in our breakdown of the best time to take NMN.

If you also use TMG, taking it alongside NMN may simply make the routine easier to remember.

Food is another area where claims can get ahead of the evidence. Current human research does not show that taking NMN and TMG together on an empty stomach gives better results than taking them with food.

Following the directions on your supplement and choosing a schedule you can stick with is the simpler approach.

Are There Any Side Effects or Risks?

Both NMN and TMG have been studied in humans, but long-term data remain limited, especially for NMN.

The 250 mg NMN trial discussed earlier reported no adverse events or abnormalities in standard blood testing during the 10-week intervention. That is reassuring, but 25 participants over 10 weeks cannot tell us everything about years of use. (1)

TMG deserves a little nuance too.

High-dose betaine can lower homocysteine, but more is not automatically better. In pooled data from randomized studies, 6 g of betaine per day for six weeks increased LDL cholesterol by about 0.36 mmol/L and triglycerides by 0.14 mmol/L compared with placebo. (6)

Another 12-week trial using 6 g daily similarly found higher total and LDL cholesterol in the betaine group compared with controls. (7)

Possible supplement concerns can also include digestive discomfort, especially at larger doses.

Talk with a healthcare professional before using NMN or higher-dose TMG if you take medication, have a medical condition, are pregnant or breastfeeding, or have abnormal homocysteine or lipid levels.

Final Words

NMN and TMG have a logical connection, but the research is not strong enough to say that every NMN user needs extra TMG. NMN supports NAD+ production, while TMG works as a methyl donor and plays a role in homocysteine metabolism. (1)(2)(4)

At Omre, we follow that same research-first approach with our NMN + Resveratrol and TMG + B-Complex formulas. They can be used as separate parts of a healthy-aging routine, depending on your goals and individual needs.

FAQs

Can I Take NMN Without TMG?

Yes. Current human research has not established that TMG is required when taking NMN. NMN metabolism involves methylation, but this alone does not prove that supplemental NMN creates a methyl-group deficiency.

Does NMN Deplete Methyl Groups?

Human studies have not demonstrated clinically meaningful methyl-group depletion from standard NMN doses. A high-dose study using 3,000 mg daily of NR, another NAD+ precursor, also found no depletion of the measured methyl-donor pool after four weeks. (3)

What Is the Best Ratio of TMG to NMN?

There is no clinically proven ratio. A 1:1 ratio is commonly discussed, but researchers have not established it as superior to other amounts or shown that TMG must be matched to the NMN dose.

Can You Take NMN and TMG at the Same Time?

Yes, they can be part of the same routine, but there is no evidence showing that taking them at precisely the same time gives better results.

Does TMG Increase NAD+?

TMG is not an NAD+ precursor. Its main relevance to NMN comes from its role as a methyl donor and its involvement in homocysteine and methionine metabolism. Research has not established that adding TMG directly raises NAD+ levels.

References

1. Yoshino M, et al. Nicotinamide mononucleotide increases muscle insulin sensitivity in prediabetic women. Science. 2021. Read the full NMN study on PubMed Central.

2. Steenge GR, et al. The effect of low doses of betaine on plasma homocysteine in healthy volunteers. British Journal of Nutrition. View the betaine dose-response study on PubMed.

3. Berven H, et al. NR-SAFE: a randomized, double-blind safety trial of high dose nicotinamide riboside in Parkinson's disease. Nature Communications. 2023. Read the full NR-SAFE study.

4. Olthof MR, et al. Betaine supplementation lowers plasma homocysteine in healthy men and women. Journal of Nutrition. View the randomized betaine study on PubMed.

5. McRae MP. Betaine supplementation decreases plasma homocysteine in healthy adult participants: a meta-analysis. Journal of Chiropractic Medicine. Read the betaine meta-analysis on PubMed.

6. Olthof MR, et al. Effect of homocysteine-lowering nutrients on blood lipids: results from four randomised, placebo-controlled studies in healthy humans. PLOS Medicine. View the lipid study on PubMed.

7. Schwab U, et al. Betaine supplementation decreases plasma homocysteine concentrations but does not affect body weight, body composition, or resting energy expenditure in human subjects. American Journal of Clinical Nutrition. Read the 12-week betaine trial on PubMed.